The present invention relates to a new method for the preparation of disubstituted amines, and more particularly to a method for the preparation of a torsemide intermediate.
Derivatives of 3-sulfonamido-4-phenylaminopyridine, of general formula I are key intermediates in the preparation of compounds with medicinally useful anti-inflammatory or diuretic properties. Some of the therapeutic properties of derivatives of this type are delineated in U.S. Pat. No. 4,018,929. An example of a medicament in this class is Torsemide (I, were R1=3xe2x80x2-methyl; R2=isopropylcarbamyl), which is marketed as an effective diuretic. 
In the prior art, compounds such as I have traditionally been prepared by the reaction of a substituted aniline with a 3-substituted-4-halo-pyridine II with or without copper catalysis, as shown in Scheme 1 (U.S. Pat. Nos. 4,018,929 and 4,244,950). However, the synthesis of the required 3-substituted-4-halo-pyridine substrates (see J. Delarge, Annales Pharmaceutiques Francaises (1973), 31, 467-474) usually presents considerable preparative challenges such as drastic reaction conditions, elevated reaction temperatures (180-200xc2x0 C.), use of toxic catalysts/reagents (HgSO4, PCl5, POCl3) and formidable purification problems. In combination, these difficulties generally result in low yields of the product being obtained. 
This problem motivated us to find and alternative process for making derivatives of 3-sulfonamido-4-phenylaminopyridine I which gives high yields and uses substrates which can be more readily prepared, using milder reaction conditions and are easier to purify.
The deficiencies present in the processes described in the prior art would be overcome if compounds such as I were prepared instead by a different approach, such as using a 3-sulfonamido-4-aminopyridine III as the substrates for the coupling with an aryl halide (Scheme 2), given that the 3-sulfonamido-4-aminopyridine component III can be easily prepared from the readily available 4-aminopyridine and without the shortcomings encountered for the preparation of the substrates II. For examples of preparations of these substrates, see C. G. Neill, et al., Tetrahedron (1998), 54, 1365-16654, and E. J. Cragoe, Jr., et al., Journal of Medicinal and Pharmaceutical Chemistry (1961), 4, 369-383. 
Unfortunately, the teachings of the prior art regarding a comparable reaction, between a substituted aniline with an aryl halide establishes that in the absence of strong electron-withdrawing groups in the aryl halide ring these compounds become less reactive (Inactivated) towards the desired condensation under the conditions previously described in the literature (for instance see, K. Nakamura et al. Synthesis (1974), 882-883; J. Lindley, Tetrahedron (1984), 40, 1433-1456; R. M. Acheson, Acridines, Interscience Division, John Wiley and Sons, New York (1956), p. 157).
Now, we have surprisingly found that 3-sulfonamido-4-arylaminopyridines such as I can be prepared by condensation of a 3-sulfonamido-4-aminopyridine III with an unactivated aryl halide such as IV when the reaction is carried out under a novel combination of reaction conditions, in the presence of an alkaline compound, a copper-containing agent, and in a protic polar solvent.
Thus, in accordance with an aspect of the present invention there is provided a process for preparing a compound of formula I: 
comprising the steps of: (i) heating a pyridine derivative of the formula III: 
with an aryl halide of formula IV 
in the presence of
(iii) an alkaline compound;
(iv) a copper-containing agent; and
(v) a protic polar solvent.
where R1 represents hydrogen or a C1-C4-alkyl or alkenyl group, R2 represents hydrogen or a group of the formula R3OOC or a group of the formula R3NHCO wherein R3 represents a C1-C4-alkyl, alkenyl or unsubstituted or substituted phenyl group, and X represents Br or I.
This process is represented by the following equation: 
In a preferred embodiment of the present invention R2is hydrogen, R1 is a 3xe2x80x2-methyl group and X is iodine, so that the aryl halide is 3-iodotoluene.
The alkaline compound includes, but is not limited to, potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide, lithium carbonate, lithium hydroxide, ammonium hydroxide and the like.
In another preferred embodiment of the present invention, the alkaline compound is potassium carbonate or potassium hydroxide. The preferred stoichiometric ratio of the alkaline compound is 1 to 5 moles per mole of compound III, more preferably 1.5 to 3.5 moles, most preferably 2.5 moles.
The copper-containing agent is one in which the copper is in a state of oxidation lower than 2. Thus, the copper may for example be in the form of the metal itself (Cuxc2x0 with oxidation state of 0) or in the form of a Cu (I) salt (Cu1 with an oxidation state of 1). Examples of these copper-containing agents include, but are not limited to, metallic copper, copper (I) oxide, copper (I) chloride, copper (I) bromide, copper (I) iodide, and copper (I) acetate. Metallic copper is the most preferred copper-containing agent for the reaction. The stoichiometry of the copper-containing agent is about 2 to 6 moles per mole of compound III, preferably 3 to 5 moles, most preferably 4 moles.
The process of the present invention is performed by heating the aryl halide and the 3-sulfonamido4-aminopyridine in the presence of a copper-containing agent in which the copper is in a state of oxidation lower than 2, and an alkaline compound in a suitable polar protic solvent.
When the reaction was carried out in the more usual solvents for this type of coupling, such as DMF, dioxane, toluene, etc., only trace amounts of the desired product I, or no product at all, was obtained. Furthermore, a number of unidentified byproducts were usually observed. Nevertheless, surprisingly we have discovered that by employing a novel combination of reaction conditions, these difficulties are resolved. In so doing, the number and amount of byproducts formed during the coupling reaction of an arninopyridine III and an aryl halide IV are substantially reduced, thereby increasing the yield of I.
Examples of polar protic solvents which are useful in the reaction of the present invention include, but are not limited to, n-propanol, isopropanol, n-butanol, amyl alcohol and ethylene glycol. n-Butanol is the most preferred solvent for this process.
The process of the present invention also uses a minimum temperature of about 80xc2x0 C. The reaction is conducted at a temperature between the range of about 80xc2x0 C. and about 180xc2x0 C. Most preferably the reaction temperature is maintained within the range of about 115xc2x0 C. to about 130xc2x0 C. The reaction is preferably carried out under an inert atmosphere, for example under argon or nitrogen.
Thus, according to a preferred embodiment of the invention, the reaction is conducted by heating at about 120xc2x0 C. a mixture of about 1.5 moles of the selected aryl halide with about one mole of the 3-sulfonamido-4-aminopyridine and about 2.5 moles of potassium carbonate in the presence of about 4 moles of copper metal and n-butanol as a solvent.
The following examples illustrates the preparation of compounds of formula I and are not to be construed as limiting the scope of the invention in any manner.